CHAPTER 140

Vesicular Exanthems

Caleb Jeon, MD; Meiling L. Fang Yuen, MD; and Ki-Young Yoo, MD

Exanthems are generalized, erythematous rashes with an underlying cause. They are most frequently caused by viral or bacterial infections. However, they can also be caused by noninfectious etiologies such as autoimmune disorders, drug reactions, genetic disorders, and physical injury. Infectious eruptions are most commonly morbilliform in the pediatric population, but they can present as vesicular, bullous, petechial, or purpuric eruptions. Vesicles are elevated, fluid-filled lesions that measure 1 cm or less (≤0.4 in) in diameter. Those that are larger than 1 cm (>0.4 in) are called bullae. Vesicles often lose their initial morphology quickly because they can break spontaneously or coalesce into bullae. They can arise de novo or from macules or papules. Vesicles may be discrete, grouped, generalized, or linear, depending on their etiology, and their specific distribution is often helpful in formulating a differential diagnosis.

History and Physical Examination

A thorough history should be obtained (Box 140.1). Health professionals must inquire about the patient’s general health as well as the specific details of the eruption.

Although the physical examination focuses on the skin, other aspects of the examination are helpful diagnostically. Vital signs should be assessed to verify the presence or absence of fever. The oropharynx should be examined closely for any lesions on the tongue, gingiva, buccal mucosa, palate, anterior tonsillar pillars, and posterior pharynx. The lips should also be examined for any evidence of vesicular lesions that may occur with a primary or recurrent herpes simplex infection.

Patients should be completely unclothed to permit a thorough examination of the skin. The distribution of the lesions should be noted. Physicians should determine whether the vesicles are grouped in a particular dermatomal distribution, as with zoster (shingles), or more generally distributed and in various stages of development, as with varicella. A linear distribution may suggest contact with poison ivy or oak. Physicians should also note the following: Do the lesions include or exclude the palms and soles? Are the buttocks involved? Are the lesions concentrated on 1 specific part of the body, such as the feet and toes or the hands? Are the sizes of the lesions uniform? If not, are other larger bullous-like lesions present in addition to vesicles? It is also helpful, if at all possible, to examine the skin of family members for similar lesions.

Vesicular exanthems are eruptions of distinctive lesions that are raised and fluid filled (Box 140.2). They may be located anywhere on the child’s body and, depending on the etiology, may or may not be pruritic. Other symptoms that may accompany such rashes include fever, upper respiratory symptoms, and gastrointestinal and central nervous system (CNS) involvement.

Epidemiology

Epidemiological factors can help differentiate infectious from noninfectious etiologies. Patient age, season of the year, presence or absence of similar cases in the community, and regular attendance at child care or school, which may contribute to exposure, should all be considered. Biological sex and ethnicity are usually less informative but can help distinguish certain diseases causing exanthems.

Primary varicella-zoster virus (human herpesvirus [HHV] 3), or chickenpox, is among the most common vesicular exanthems seen in childhood. Males and females are equally affected. Most reported cases in the pre-vaccine era were in children younger than 10 years. Since universal vaccination has been implemented, children aged 10 to 14 years are becoming the group with the greatest incidence of infection, although it is still less than during the pre-vaccine period. It is primarily transmitted person-to-person by airborne spread of aerosolized viral particles from vesicles of infected persons. It may also be transmitted through respiratory secretions and vertically from mother to fetus. It is extremely infectious, and transmission to susceptible household contacts is greater than 90%. The incubation period ranges from 10 to 21 days after exposure but can be longer (21–28 days) if varicella-zoster immune globulin is administered. Neonates born to mothers with active infection around the time of delivery can develop varicella 2 to 16 days after birth. Patients are considered contagious from 1 to 2 days before onset of cutaneous lesions until all are crusted over.

Human herpesvirus 1 and 2, also called herpes simplex virus (HSV), affect most adults worldwide. Historically, HHV-1 infections generally occurred outside the genital area and HHV-2 within the anogenital area. Now, either virus can be found in both areas. Neonatal infection is generally acquired at delivery from an infected mother who is often unaware of her infection. Human herpesvirus 1 is typically transmitted by direct contact with oral secretions or lesions and HHV-2 from direct contact with infected genital secretions. Shedding of viral particles can occur in the absence of active infection. The incubation for HHV infection beyond the neonatal period is 2 days to 2 weeks. Most affected neonates will have signs of clinical infection in the first postnatal month.

Hand-foot-and-mouth disease and herpangina are caused by enteroviral infections and occur worldwide. Outbreaks involving child care centers, schools, summer camps, hospital wards, military installations, communities, large geographic areas, and entire countries have been reported. They are transmitted person-to-person by the fecal-oral route. They also can be transmitted by contact with oral and respiratory secretions and, in the case of hand-foot-and-mouth disease, vesicle fluid. Most cases of these 2 conditions occur in infants and children. Hand-foot-and-mouth disease is most commonly caused by infection with coxsackievirus A16 or enterovirus 71 and is among the most recognizable viral exanthems in children and adults. The principal enterovirus serotypes associated with herpangina are coxsackieviruses A1 to A6, A8, A10, and A22. These enteroviral infections occur most commonly in summer and early fall. The usual incubation period for most enteroviruses is between 3 and 6 days.

Diagnosis and Differential Diagnoses

Primary Varicella-Zoster Virus (Chickenpox)

Primary varicella-zoster virus (chickenpox) infection usually consists of hundreds of vesicles, existing in various stages of resolution. Lesions progress from erythematous macules and papules to vesicles and, eventually, to pustules that then crust and heal normally without scarring unless secondarily infected and deeply inflamed. Characteristically, the vesicle has been described as a “dewdrop on a rose petal.” Associated prodrome includes malaise and mild fever. Symptoms tend to be more severe in infants and older patients. Since universal vaccine implementation, breakthrough cases have become more common and have a milder clinical presentation. Fetal infection during the first or early second trimester can result in fetal demise or in congenital varicella syndrome, consisting of limb hypoplasia, cutaneous scarring, ophthalmic abnormalities, and CNS defects. Infection acquired from 5 days antepartum to 2 days postpartum can also be fatal because of the absence of protective maternal antibodies. Bullous varicella can result when Staphylococcus aureus infects the vesicles of chickenpox, with greater chance of scarring.

Modified varicella, also known as “breakthrough varicella,” can occur in vaccinated people. Breakthrough varicella is usually milder than natural varicella, with less than 50 lesions, low or no fever, and shorter duration of rash. Most studies have noted breakthrough varicella occurring in fewer than 1% to 3% of vaccinated children each year after vaccination. The rash may be atypical in appearance with fewer vesicles and predominance of maculopapular lesions. Breakthrough varicella is contagious, although less frequently transmitted than natural varicella.

Herpes zoster, a reactivation of a latent infection with varicella-zoster virus, can also cause a vesicular rash. The virus, which rests dormant in neuronal cells, travels along the nerves when reactivated and becomes released into the skin. It is generally a disease of older people, although children can be affected. In zoster, the lesions are grouped unilaterally in the distribution of 1 to 3 sensory derma-tomes. It can be quite painful, and postherpetic neuralgia can last for months. In immunocompromised patients, the rash of zoster can become disseminated.

Human Herpesvirus 1 and 2 (Herpes Simplex Virus)

The onset of clinical illness of HSV-1 is usually sudden, with the appearance of multiple characteristic vesicular lesions superimposed on an inflammatory, erythematous base. Primary infection may also be associated with systemic symptoms, such as fever and malaise. The lesions can be painful and last for 10 to 14 days. Vesicles are usually grouped in a single anatomical site; however, autoinoculation of distant locations can occur. Although the symptoms can be severe, most primary HSV-1 infections are asymptomatic. Once HSV infection has occurred, the virus lives in a latent state in nerve cell bodies in ganglion neurons and can reactivate. The frequency and severity of reactivation is determined by many factors, including immunodeficiency or stress.

The clinical manifestations of primary genital HSV infection are highly variable. The initial presentation can be severe with painful genital ulcers, dysuria, fever, and tender local inguinal lymphadenopathy. In other patients, however, the infection is mild, subclinical, or entirely asymptomatic. There are no clear differences in clinical presentation based on infecting virus (ie, HSV-1 vs HSV-2).

Disseminated, CNS, or skin, eyes, and/or mouth HHV infection in an infant is usually caused by HHV-2, very severe, and often accompanied by skin findings. In children and adolescents, HHV-1 gingivostomatitis and perioral vesicles are the most common clinical findings and can also be asymptomatic. A prodrome of paresthesia with recurrent infection is not uncommon. There can also be an ulcerative enanthema. Human herpesvirus 1 and 2 persist for life in the sensory ganglia and, when reactivated, result in single or grouped vesicles, often on the vermilion border with an erythematous base. Triggers include stress, UV exposure, and fever.

Hand-foot-and-mouth Disease and Herpangina

Hand-foot-and-mouth disease is associated with a brief, mild prodrome of fever, malaise, and mouth pain. The exanthem consists of erythematous macules and papules with a central gray vesicle. Generally, the volar surfaces of the hands and feet, as well as the buttocks, tend to be involved. In a recent North American 2011–2012 epidemic, infection with coxsackievirus A6 resulted in hand-foot-and-mouth disease with more extensive areas of cutaneous involvement and more protean morphologies, as well as localization to areas of active dermatitis, termed “eczema coxsackium.” The concomitant enanthema is seen on the tongue, buccal mucosa, palate, uvula, and anterior tonsillar pillars. In herpangina, patients acutely develop fever, malaise, headache, and neck pain. There is a painful enanthema of small grayish-white vesicles on the soft palate, uvula, buccal mucosa, pharynx, and tonsils. These ulcerate with a surrounding red halo.

Bullous Impetigo

Impetigo is the most common bacterial skin infection in children. Bullous impetigo is a less common form of impetigo than the non-bullous forms. Bullous impetigo is most frequently seen in the summer in warm, humid conditions and is easily spread among individuals in close contact. The infection may be classified as primary impetigo (direct bacterial invasion of previously normal skin) or secondary impetigo (superinfection at sites of minor skin trauma such as abrasions, minor trauma, and insect bites, or underlying conditions such as eczema) and is also sometimes referred to as impetiginization. There can be associated fever, weakness, and diarrhea, although there are often no systemic symptoms. Small vesicles enlarge rapidly into flaccid bullae that easily rupture. These lesions can be generalized and can arise from normal-appearing skin. The infection is usually caused by S aureus, phage group 2, and is a localized reaction to exfoliative toxin that causes loss of cell adhesion in the superficial epidermis by targeting the protein desmoglein 1. This condition affects mostly neonates, infants, and younger children.

Scabies

Scabies is transmitted during prolonged close contact with an infested individual. Scabies has an incubation period of 4 to 6 weeks in patients without previous exposure. Reexposed patients develop symptoms a few days after repeat exposure. Caused by the tiny mite Sarcoptes scabiei, it can cause an intensely pruritic, generally papular eruption, although vesicular lesions can occur. Commonly, secondary excoriations are seen (see Chapter 138). In older children and adults, interdigital folds, flexor wrists, waistline, trunk, and genital area are more commonly affected. A linear burrow is pathognomonic but often difficult to identify clinically. Patients younger than 2 years have involvement predominantly of the head, neck, palms, and soles. In this age group, the eruption is more likely to be vesicular. Arthropod bites can also result in isolated and scattered vesicles.

Fungal Pathogens

Fungal pathogens that cause tinea pedis include Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, and Epidermophyton floccosum. Infection can directly cause a scaly or vesicular rash or can result in a hypersensitivity reaction to the fungi, presenting as vesicles on the palms, soles, sides of the fingers, and, occasionally, on the extremities and trunk. Trichophyton mentagrophytes can cause vesicles and bullae on the medial foot. It can be associated with an id reaction, in which deep-seated pruritic vesicles develop secondary to tinea infection elsewhere. An id reaction, most commonly on the hands, face, and trunk, can also result from tinea capitis, usually caused by T tonsurans and Microsporum canis, although it does not cause a vesicular exanthem on its own (see Chapter 136). The incubation periods of fungal infections are variable, and exact limits are unknown.

Pompholyx (Dyshidrotic Eczema)

Pompholyx (dyshidrotic eczema) is a disease that can occur in children with chronic eczematous dermatitis or atopic dermatitis but can occur in children who are nonatopic as well. The clinical appearance of pompholyx can be identical to that of an id reaction or fungal infection and consists of tapioca, pearl-like, deep-seated vesicles frequently seen on the palms and soles as well as the lateral sides of the fingers that are extremely pruritic. Secondary impetiginization (bacterial superinfection) is common. Cases can be acute and recurrent, as well as chronic.

Allergic Contact Dermatitis

A delayed type IV hypersensitivity reaction secondary to contact with plants of the genus Toxicodendron is a common cause of allergic contact dermatitis. The main allergen in these plants is a catechol. Rhus dermatitis is the prototypical allergic contact dermatitis, which develops about 1 to 3 days after exposure to plants such as poison ivy, oak, and sumac. Linear papules and vesicles are seen at points of contact between the plant antigen and the skin (see Chapter 138). Contact with other allergenic substances may also produce a vesicular rash, including nickel, rubber compounds, fragrances, and preservatives in cosmetics.

The differential diagnosis of acute vesicular exanthems can be organized according to the distribution of the lesions. Distinctive locations, as well as specific patterns, are important to consider in each individual case. The presence or absence of fever can assist in developing the appropriate differential diagnosis (Figure 140.1 and Box 140.3). Epidemiological as well as historical information may suggest the diagnosis. For example, known exposure to varicella-zoster virus (chickenpox) 10 to 21 days prior to a vesicular eruption facilitates diagnosis of this disease. A history of hiking, camping, or other outdoor activities suggests possible contact with poison ivy or oak. In addition, the presence of a specific prodrome can often be elicited with primary or recurrent herpes simplex. Pain on swallowing often occurs with enteroviral infection. A history of similar lesions lessens the likelihood of acute primary infection and suggests a chronic condition such as the recurrent disorder pompholyx.

Laboratory Tests

Typically few, if any, laboratory studies are necessary in healthy children with vesicular eruptions because the diagnosis is often made clinically. Clinical diagnosis is becoming more challenging because of fewer cases of varicella and milder, atypical cases in the vaccinated population. A Tzanck test of the base of a vesicle showing multinucleated giant cells may be useful in making a preliminary diagnosis of herpes simplex or varicella. Direct fluorescent antibody and polymerase chain reaction are rapid methods to diagnose varicella. Polymerase chain reaction can detect viral DNA from swabs of vesicles or scabs. This test is highly sensitive and widely available. Culture and polymerase chain reaction should be obtained for diagnosis of neonatal herpes simplex infection.

Definitive confirmation of scabies can be made by microscopic examination of skin scrapings from suspicious lesions. The presence of the adult mite or ova, larvae, nymphs, or feces (scybala) is diagnostic. For children with suspected tinea pedis, scale collected from a skin scraping can be prepared with potassium hydroxide and examined under the microscope. Fungal cultures can also be obtained.

Figure 140.1. Approach to the evaluation of vesicular eruptions.

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